application) One of the major goals of our ADRC is to understand the biological substrates of mutant genes associated with impairments of cognition and memory. Project 2 takes advantage of the availability of several independent lines of mice (El-2 and C3-3) expressing a chimeric Mo/Hu-APP-695 polypeptide that harbors the Swedish double mutation (KM 570-571 NL). These mice express the mutant APP (Mo/Hu-APPswe) at levels approximately threefold greater than endogenous mouse APP and, between 20 and 24 months of age, develop AB42-immunoreactive deposits and associated cellular abnormalities. The investigators have controlled for the homogeneity of genetic background by back-crossing our transgene array into C57BL/6J mice for ten generations to obtain mice that are 99.99% congenic. Because their preliminary behavioral studies of Mo/Hu-APPswe Tg mice have documented the presence of mild memory deficits that antedate AB deposition, they hypothesize that shifts in levels of AB species, which occur significantly before AB deposition, are accompanied by subtle structural alterations in the neuropil (synaptic terminals/neurites) and that these lesions impact on behavioral performance. After the performance of these Tg mice is assessed in tasks of cognition/memory, animals will be sacrificed, and tissues will be analyzed for regional changes in biochemical markers (e.g., levels of AB peptide species, synaptic proteins, neurotransmitters and their enzymes) and the character/severity of the cellular pathology (e.g., abnormalities in synapses, AB deposition, reductions in synapses, loss of subsets of neurons, evidence of cell death, activation of glial cells, etc.) in specific regions of brain. They believe that these clinical-neurochemical-pathological correlations will help to define the biological substrates of impairments in these mice, and this information will provide important insight into similar processes that occur in elderly humans, particularly in the preclinical and early stages of disease.
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